Until tuberculosis is controlled worldwide, it will continue to be a major killer in less developed countries and a constant threat in most of the more-developed countries. It has been reported that 2 billion people are latently infected and 1 in 10 latent infections will progress to the active disease. Mycobacterium tuberculosis, the causative agent for tuberculosis (TB), infects one-third of the world's population, resulting in eight to nine million new cases of active TB and two million deaths each year (Kremer, et al., Expert Opin. Investig. Drugs, 11, 1033-1049 (2002); and Frieden, T. R., et al., The Lancet, 362, 887-99 (2003); and Diacon, Andreas H., et al., N Eng J Med. 360(23), 2397-2405 (2009)). TB is presently treated with a four-drug combination (isoniazid, rifampin, pyrazinamide, ethambutol) that imposes a lengthy 6-9 month treatment course, often under the direct observation of a healthcare provider (Davies, et al., Expert Opin. Investig. Drugs. 12, 1297-1312 (2003)). The major shortcoming of this regimen is the long treatment time (up to 2 years) and high failure rate, which makes patient compliance and proper implementation a challenge. More than two-thirds of the TB patients do not receive full and proper TB treatment, which results in a high relapse rate and emergence of drug resistance.
About 4% of the TB cases worldwide are multiple-drug resistant (MDR), e.g., resistant to both isoniazid and rifampicin. XDR-TB, an abbreviation for extensively drug-resistant tuberculosis (TB), is a form of TB which is resistant to at least four of the core anti-TB drugs. XDR-TB involves resistance to the two most powerful anti-TB drugs, isoniazid and rifampicin (MDR-TB), in addition to resistance to any of the fluoroquinolones (such as ofloxacin or moxifloxacin) and to at least one of three injectable second-line drugs (amikacin, capreomycin or kanamycin). Although XDR-TB is more rare, 77 countries worldwide had reported at least one case by the end of 2011. The World Health Organization (WHO) estimates that there are about 650,000 MDR-TB cases in the world at any one time. The number of cases of MDR tuberculosis is alarmingly increasing worldwide, with MDR detected in up to 35% of newly diagnosed cases and in 76.5% of patients who had previously been treated for tuberculosis. XDR tuberculosis was identified in 14% of patients with MDR, with patients less than 35 years old exhibiting an odds of MDR tuberculosis that was 2 times that for individuals aged over 35 years. See, Uhlin, M., et al., J Infect Dis, 205(Suppl 2), S325-334 (2012).
MDR-TB and XDR-TB both take substantially longer to treat than ordinary (drug-susceptible) TB, and require the use of second-line anti-TB drugs, which are more expensive and have more side-effects than the first-line drugs used for drug-susceptible TB. Treatment is complex and requires longer use of more-expensive, less effective, and toxic anti-tuberculosis drugs, which results in high morbidity and mortality.
There still remains several issues that need to be addressed in both standard TB therapies as well as MDR/XDR resistant therapies. For example, there is a need to shorten the duration of standard TB therapy which could increase compliance and thus reduce resistance. For MDR/XDR resistant TB, there is an unmet need to find novel chemotypes that are active against MDR and XDR TB that enhance cure rate, reduce adverse effects, shorten treatment time, and improve patient compliance which reduces resistance.